Flavonoids, esophageal/gastric cardia adenocarcinoma and Barrett's esophagus risk ABSTRACT. The incidence of esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) has increased more rapidly than any other cancer in the United States and other Western countries over the past 30-40 years. EA and GCA appear to develop from normal mucosal lining through a sequence of pathologic events. The normal squamous mucosa is believed to be destroyed by chronic gastroesophageal reflux disease (GERD), which can cause ulceration of the esophagus followed by development of Barrett's esophagus (BE). BE is the only known potential precursor of these cancers of the gastroesophageal junction, and the incidence of BE is also increasing. Epidemiologic studies have shown that diets high in fruit and vegetable consumption are inversely associated with EA/GCA and BE. It is hypothesized that flavonoids, which are a group of bioactive polyphenolic compounds that are naturally occurring in fruits, vegetables, and beverages of plant origin, partially account for the risk reduction of fruits and vegetables on these tumors. Experimental studies have supported this hypothesis and have shown that flavonoids regulate cell cycle, proliferation, and apoptosis, which have important chemotherapeutic effects against these tumors. A number of flavonoids are also COX-2 inhibitors and some can suppress COX-2 transcription. Epidemiologic studies have shown a modest reduction in risk of EA/GCA and BE in users of non-steroidal anti-inflammatory drugs (NSAIDS), including aspirin, which are COX-2 inhibitors. However, NSAIDS can have severe side effects so their clinical usage is limited. Therefore, it is of interest to develop a preventin strategy for these tumors that is acceptable for general use. To investigate this potential association between flavonoids and EA/GCA and BE, an ancillary study will be performed to address two specific aims. The first specific aim will determine whether flavonoid consumption is associated with EA/GCA risk from data that was collected as part of a multicenter, population-based case-control study conducted in Connecticut, New Jersey, and western Washington State. The parent study included 293 EA subjects, 261 GCA subjects, and 695 frequency matched control subjects. The second specific aim will determine whether flavonoid consumption is associated with BE risk from data that was collected in a case-control study conducted in western Washington State. The parent study included 193 BE subjects and 211 individually matched control subjects. The two parent case-control studies assessed usual dietary intake using a similar validated food frequency questionnaire (FFQ). For the proposed study, two flavonoid-specific databases will be developed by linking each FFQ on frequency of dietary intake and portion size with existing USDA flavonoid databases. If we are able to demonstrate that total flavonoids or a class of flavonoids are associated with BE or EA/GCA, there is potential to use flavonoids as a risk reduction strategy. This would allow some EA and GCA to be prevented before individuals develop these lethal cancers. PUBLIC HEALTH RELEVANCE: Esophageal and gastric cardia adenocarcinoma have very poor survival prognoses (normally less than a year), and the only known potential precursor of these cancers is Barrett's esophagus. If we can show an association between flavonoids, which are a naturally occurring compound found in fruits and vegetables, and esophageal adenocarcinoma, gastric cardia adenocarcinoma, or Barrett's esophagus, there is potential to use flavonoids as a risk reduction strategy. This would allow some esophageal or gastric cardia adenocarcinoma to be prevented before individuals develop these deadly cancers.